My background and postgraduate training present a strong foundation for a future in academic medicine. I obtained a combined M. D. and Ph.D. (in Biochemistry) degrees at Case Western Reserve University, and then completed a residency in Internal Medicine and a clinical Fellowship in Rheumatology at University Hospitals of Cleveland. I have now returned to the laboratory environment to solidify my skills in immunology. I have consistently maintained an interest in basic research as I have been able to contribute to several publications during my clinical training. This award will provide me with the final training in immunology that will allow me to become an independent clinician scientist. The focus of this proposal is to define, characterize, and manipulate CD8 immune responses with an ultimate goal of applying our findings to the understanding the immune response to Hepatitis C infections. Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States. The CD8 T cell immune response directed at HCV-derived antigens in the infected host is thought to be important for effectively controlling viral replication and possibly for clearing the viral infection. Despite this, there is a relative paucity of published information on the frequency, fine antigen specificity, and cytokine-producing character of the HCV-specific CD8 T cell immune response in affected individuals. An improved understanding of these issues is required to permit appropriate design of studies aimed at enhancing the anti-viral immune response and preventing or treating HCV infections. Moreover, current prognostic indicators of HCV infection are few in number, are inadequate to accurately predict morbidity and mortality outcomes, and are suboptimal for aiding in making treatment decisions. Our laboratory is studying T cell immune responses in both mouse models and human peripheral blood lymphocytes through the use of an ELISA spot assay with single cell resolution. As shown by our preliminary data, we can readily detect, quantify and determinant map CD8 T cell responses using this approach. We hypothesize that the emergence of HCV antigen-specific T cell immunity is essential for effective control of HCV infections resulting in prevention of progression of this disease. We further hypothesize defining CD8 T cell epitopes through comprehensive determinant mapping will permit targeted manipulation of relevant immune responses aimed at preventing and/or treating HCV infections in humans. To investigate these hypotheses, will 1) characterize the induced CD8 T cell immune response after priming mice with antigens in the context of MHC I, 2) determine how different immunization protocols with known MHC I-restricted peptide determinants affects the cytokine profile and effector functions of the induced CD8 T cell immune response in the mouse, and 3) identify and characterize CD4 and CD8 T cell epitopes from HCV core protein in humans infected with HCV.